DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Requirement for Information
Applicant and the assignee of this application are required under 37 CFR 1.105 to provide the following information that the examiner has determined is reasonably necessary to the examination of this application.
In response to this requirement, please provide a copy of the poster titled “Isolation and Characterization of a TDP1 Inhibitory Peptide from the Marine Sponge Axinella sp” presented by LR Krumpe, S Sunassee, A Bermingham, C Marchand, KR Gustafson, Y Pommier, and BR O'Keefe on Wednesday, September 16, 2015, at the NIH Research Festival. A copy of this poster is required to determine patentability of the claims because based on the abstract of the poster, it appears to make publicly available the peptide Recifin A that this the subject of and claimed in the instant application. This poster was presented outside of the grace period of the instant application by several of the inventors of this application.
In response to this requirement, please provide copies of each publication which any of the inventors authored or co-authored and which describe the disclosed subject matter of peptides of SEQ ID NOs: 1, 7-9, 11-12, and 16, especially recifin A. It is noted that a prior art search yielded the above referenced poster, which was made publicly available outside of the grace period of the instant application by several of the inventors of this application. Despite its clear relevance to patentability and authorship by the inventors, the poster was not cited on the IDS. Applicant must provide all other similar disclosures made by the inventor.
The applicant is reminded that the reply to this requirement must be made with candor and good faith under 37 CFR 1.56. Where the applicant does not have or cannot readily obtain an item of required information, a statement that the item is unknown or cannot be readily obtained may be accepted as a complete reply to the requirement for that item.
This requirement is an attachment of the enclosed Office action. A complete reply to the enclosed Office action must include a complete reply to this requirement. The time period for reply to this requirement coincides with the time period for reply to the enclosed Office action.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-3, 5-6, 11-14, 19, and 27 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
BRI of the claims includes the knotted cyclic peptide recifin A from the marine sponge Axinella sp.:
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as evidenced by Krumpe et al. (Recifin A, Initial Example of the Tyr-Lock Peptide Structural Family, Is a Selective Allosteric Inhibitor of Tyrosyl-DNA Phosphodiesterase I. J. Am. Chem. Soc. 2020, 142, 50, 21178–21188).
Regarding claim 1, recifin A comprises a peptide of instant SEQ ID NO: 1 wherein X1 is phenylalanine (Figure 3).
Regarding claims 2 and 13, recifin A has a fold comprising a four strand antiparallel β-sheet and two helical turns stabilized by a complex disulfide bond network that creates an embedded ring around one of the strands, as evidenced by Krumpe et al. (Figure 5).
Regarding claim 3, recifin A comprises a peptide of instant SEQ ID NO: 7 (Figure 3).
Regarding claims 5 and 11, recifin A comprises an amino acid sequence that has about 85% identity to instant SEQ ID NO: 1 (i.e. each of the six iodoacetamide alkylated cysteines in SEQ ID NO: 1 are substituted with cysteine).
Regarding claim 6, recifin A comprises instant SEQ ID NOs: 7, 8, 9, and 12, and is identical to instant SEQ ID NO: 16.
Regarding claim 12, recifin A comprises a peptide identical to instant SEQ ID NO: 16 with deletion of residue 1, residues 1-2, residues 1-3 or residues 1-4.
Regarding claim 14, BRI of “not naturally occurring” includes a synthetic recifin A, which has the amino acid sequence of SEQ ID NO: 16 but is synthesized chemically rather than occurring in nature.
Regarding claim 27, a nucleic acid that encodes recifin A in part of the genome for the marine sponge Axinella sp., as evidenced by Krumpe et al.
Step 1: Claims 1-3, 5-6, 11-14, and 27 are to a composition of matter.
Step 2A, Prong 1: Claims 1-3, 5-6, and 11-14 are directed to a product of nature, the peptide recifin A. Claim 27 is directed to a product of nature, a nucleic acid encoding recifin A. The closest counterpart to the nature-based product is recifin A (or the nucleic acid encoding it) in the marine sponge Axinella sp. The claimed peptide (nucleic acid) is structurally identical to the natural peptide (nucleic acid), e.g., they had the same peptide (nucleic acid) backbone and amino acid (nucleotide) sequence as recifin A (or the nucleic acid encoding it) in nature. In addition, the function of the claimed peptide (nucleic acid), inhibition of TDP1 (encoding recifin A), is innate to the peptide (nucleic acid) itself, and was not created or altered by the inventor. In sum, the claimed peptides (nucleic acid) are different, but not markedly different, from their naturally occurring counterparts and thus are natural phenomenon exceptions
Step 2A, Prong 2: The claim only recites the peptide (nucleic acid), which is a natural phenomenon exception. Because there are no additional claim elements besides the judicial exception, the judicial exception is not integrated into a practical application (MPEP § 2106.04(d)(III)).
Step 2B: The claim only recites the peptide (nucleic acid), which is a natural phenomenon exception. Because there are no additional claim elements besides the judicial exception, the claim does not amount to significantly more than the judicial exception (MPEP § 2106.05).
Therefore, 1-3, 5-6, 11-14, and 27 are patent ineligible.
Regarding claim 19, BRI of the claim includes the peptide recifin A and a carrier such as water.
Step 1: Claim 19 is to a composition of matter.
Step 2A, Prong 1: Claim 19 is directed to a product of nature, the peptide recifin and the pharmaceutically acceptable carrier, which may be a nature-based product such as water. Because the peptide and water as claimed are not found together in nature, the closest counterpart to the nature-based products is recifin A and water. As determined in the analysis above, the claimed peptide is different, but not markedly different from recifin A in nature. There is no evidence on record that mixing the claimed peptide with water changes the structure, function, or other properties of either the peptide or water in a marked way. Thus, for at least one embodiment of the claim with the BRI (e.g. wherein the carrier is water), the claimed mixture as whole does not display markedly different characteristics compared to the naturally-occurring counterparts. Instead, the peptide and water have the same characteristics in the mixture as the individual components, the same chemical structure and the same function of inhibiting TDP1 and being a solvent. See Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130, 76 USPQ 280, 281 (1948). Accordingly, each component, the peptide and the carrier, is a natural phenomenon exception.
Step 2A, Prong 2: The claim only recites the peptide and the carrier, which are natural phenomenon exceptions. Because there are no additional claim elements besides the judicial exceptions, the judicial exceptions are not integrated into a practical application (MPEP § 2106.04(d)(III)). In addition, because the limitation pharmaceutical composition does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration (MPEP § 2106.04(d)(2)).
Step 2B: Prior to applicant’s invention and at the time of filing the application, using a carrier for a peptide was well-understood, routine, and conventional. Because mixing the peptide with a carrier at this high level of generality does not meaningfully limit the claim, the claim does not amount to significantly more than the judicial exception (MPEP § 2106.05). In addition, because the limitation pharmaceutical composition does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration (MPEP § 2106.04(d)(2)).
Therefore, claim 19 is patent ineligible.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 6, 11-14, 19, and 27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Krumpe et al. (Isolation and Characterization of a TDP1 Inhibitory Peptide from the Marine Sponge Axinella sp. Abstract for a Poster presented at the NIH Research Festival on Wednesday, September 16, 2015; hereafter Krumpe 2015), as evidenced by Krumpe et al. (Recifin A, Initial Example of the Tyr-Lock Peptide Structural Family, Is a Selective Allosteric Inhibitor of Tyrosyl-DNA Phosphodiesterase I. J. Am. Chem. Soc. 2020, 142, 50, 21178-21188; hereafter Krumpe 2020).
Krumpe 2015 teaches a peptide isolated from a marine sponge, Axinella sp. with inhibitory activity against Tyrosyl-DNA phosphodiesterase 1 (TDP1). Krumpe 2015 teaches that the peptide is 4.9 kDa peptide.
Krumpe 2015 is silent regarding the amino acid sequence of the peptide.
MPEP § 2131.01(III) states: A rejection under 35 U.S.C. 102 over multiple references is proper when the extra reference or other evidence can be used to show an inherent characteristic of the thing in the primary reference. "To serve as an anticipation when the reference is silent about the asserted inherent characteristic, such gap in the reference may be filled with recourse to extrinsic evidence. Such evidence must make clear that the missing descriptive matter is necessarily present in the thing described in the reference, and that it would be so recognized by persons of ordinary skill." Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1268, 20 USPQ2d 1746, 1749-50 (Fed. Cir. 1991). The critical date of extrinsic evidence showing a universal fact need not antedate the filing date. See MPEP § 2124.
A post-filing date reference published by the same authors, Krumpe 2020, states that the molecular weight of a peptide isolated from marine sponge, Axinella sp. and having inhibitory activity against TDP1 has a molecular weight of 4912.9661 Da. This peptide, called Recifin A, is identical to instant SEQ ID NO: 16. Given that the peptide disclosed in the prior art abstract is isolated from the same organism, has the same activity, and the same molecular weight as Recifin A, the peptide in the prior art abstract must possess the property of having the same amino acid sequence as Recifin A, instant SEQ ID NO: 16.
Therefore, the peptide in Krumpe 2015 meets all of the limitations of instant claims 1-3, 6 and 13.
Regarding claim 11, SEQ ID NO: 16 comprises SEQ ID NO: 1 with six substitutions.
Regarding claim 12, SEQ ID NO: 16 comprises SEQ ID NO: 16 with a deletion of 1-4 residues at the N-terminus.
Regarding claim 14, BRI of not naturally occurring includes isolated and purified.
Regarding claim 19, the peptide in a carrier for a TDP1 inhibition assay is a pharmaceutical composition.
Regarding claim 27, the nucleic acid encoding the peptide is present in the marine sponge taught by the reference.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6, 11-19, 22-23, and 27-29 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The nature of the invention
The claimed invention is the result of high-throughput screening for TDP1 inhibitors that yielded a new class of knotted cyclic peptides from the marine sponge, Axinella sp. The claims are drawn to knotted cyclic peptides, pharmaceutical compositions comprising them, methods of making them by recombinant expression and fragment ligation chemistry, and methods of using them to inhibit TDP1 activity in a mammal and to treat and prevent cancer.
Scope of the claims
Claim 1 is drawn to a knotted cyclic peptide comprising CX1X2XXXCXXXXXXXXXCCXXXXXXSXXLXXXXXXCXXC (SEQ ID NO: 11), wherein X is any amino acid and one of X1 and X2 is tyrosine, phenylalanine, or alanine. The genus of SEQ ID NO: 11 contains 2029 (5.4 x 1037) unique amino acid sequences. BRI of the term “knotted cyclic peptide” is a closed-ring structure formed by disulfide bonds between the cysteines in the amino acid sequence. The term is not limited to a particular number or connectivity of disulfides. There are no functional limitations in this claim.
Claim 2 is drawn to a having an amino acid sequence of claim 1 that adopts a three-dimensional structure having a four strand anti-parallel b-sheet and two helical turns. There are no functional limitations in this claim.
Claim 3 is drawn to a knotted cyclic peptide comprising SEQ ID NO: 7. The genus of SEQ ID NO: 7 contains 2028 (2.7 x 1036) unique amino acid sequences. There are no functional limitations in this claim.
Claim 4 is drawn to a knotted cyclic peptide comprising SEQ ID NO: 1 with an N-terminal truncation of 1, 2, 3, or 4 amino acids. The genus of claim 4 contains four unique amino acid sequences. There are no functional limitations in this claim.
Claim 5 is drawn to a knotted cyclic peptide comprising SEQ ID NO: 11 that is not SEQ ID NO: 1. The genus of claim 5 contains one fewer sequence than the genus of SEQ ID NO: 11, which contains 2029 (5.4 x 1037) unique amino acid sequences. There are no functional limitations in this claim.
Claim 6 is drawn to a knotted cyclic peptide comprising SEQ ID NO: 7, 8, 9, 12, or 16. The genus of SEQ ID NO: 7 contains 2028 (2.7 x 1036) unique amino acid sequences. The genus of SEQ ID NO: 8 contains 2019 (5.2 x 1024) unique amino acid sequences. The genus of SEQ ID NO: 9 contains 2024 (1.7 x 1031) unique amino acid sequences. The genus of SEQ ID NO: 12 contains 2016 (6.6 x 1020) unique amino acid sequences. SEQ ID NO: 16 is a single sequence. There are no functional limitations in this claim.
Claim 11 is drawn to a knotted cyclic peptide comprising SEQ ID NO: 1 with 1-6 optional substitutions or deletions. Although this genus appears limited it is actually enormous. SEQ ID NO: 1 is 42 amino acid residues in length. A combination of any 1-6 of the 42 amino acid residues in SEQ ID NO: 1 can be substituted with any other the other 19 amino acids or deleted (20 modifications possible per position modified).
If six amino acid residues are substituted or deleted there are 206 (6.4x107) sets of modifications, if five then 205 (3.2x106) sets of modifications, if four then 204 (160,000) sets of modifications, if three then 203 (8000) sets of modifications, if two then 202 (400) sets of modifications, if one then 20 (20) sets of modifications.
Any of the 42 amino acid residues in SEQ ID NO: 1 can be modified. The number of ways to choose r items (the number of amino acid residues modified) from a set of n items (the number of amino acids total in the SEQ ID NO: 1) without regard to order is determined by the combination formula:
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. Based on this formula there are 5,245,786 combinations of six amino acid residues that can be substituted or deleted in SEQ ID NO: 1, 850,668 combinations for five substitutions or deletions, 111,930 combinations for four substitutions or deletions, 11,480 combinations for three substitutions or deletions, 861 combinations for two substitutions or deletions, and 42 combinations for one substitution or deletion.
The total number of peptides of SEQ ID NO: 1 with six substitutions or deletions is
(the number of sets of six modifications) x (the number of combinations of six amino acid residues that can be substituted or deleted in SEQ ID NO: 1)
= 6.4x107 x 5,245,786 = 3.4x1014 unique peptides. For five substitutions or deletions in SEQ ID NO: 1 there are 3.2x106 x 850,668 = 2.7x1012 unique peptides. For four substitutions or deletions in SEQ ID NO: 1 there are 160,000 x 111,930 = 1.8x1010 unique peptides. For three substitutions or deletions in SEQ ID NO: 1 there are 8000 x 11,480 = 9.2x107 unique peptides. For two substitutions or deletions in SEQ ID NO: 1 there are 400 x 861 = 3.4x105 unique peptides. For one substitution or deletion in SEQ ID NO: 1 there are 20 x 42 = 840 unique peptides. There are no functional limitations in this claim.
Claim 12 is drawn to a peptide of SEQ ID NO: 6 with one or more of modifications (a)-(g) or one or more of modifications (a)-(c). There are no functional limitations in this claim.
Claim 13 is drawn to a having an amino acid sequence of claim 1 that comprises a disulfide bond network that adopts a three-dimensional structure having an embedded ring structure. There are no functional limitations in this claim.
Claim 14 is a non-natural peptide of claim 1. BRI of non-natural includes synthesized, isolated, and purified peptides otherwise found in nature as well as peptides not found in nature. There are no functional limitations in this claim.
Claims 15-18 encompass all of the 2029 (5.4 x 1037) unique amino acid sequences of claim 1 with an additional structural modification (modified with a cell-penetrating peptide, modified with a cell-penetrating peptide at the N-terminus, modified with polyethylene glycol, modified with at least one ethylene glycol at the N-terminus, respectively). These claims do not limit the function of the peptide of claim 1.
Claim 19 is drawn to a pharmaceutical composition comprising a peptide of claim 1 and a carrier. The claim encompasses all of the 2029 (5.4 x 1037) unique amino acid sequences of claim 1.
Claim 22 is drawn to a method of treating or preventing any type of cancer in a mammal using one of the 2029 (5.4 x 1037) unique amino acid sequences of claim 1.
Claim 23 is drawn to a method of inhibiting cleavage of phosphodiester bonds by enzyme tyrosyl-DNA phosphodiesterase 1 in a mammal using one of the 2029 (5.4 x 1037) unique amino acid sequences of claim 1.
Claim 27 is drawn to a nucleic acid encoding one of the 2029 (5.4 x 1037) unique amino acid sequences of claim 1. The claim does not limit the function of the peptide encoded by the nucleic acid.
Claim 28 is drawn to a method of making a peptide of claim 1 by expressing a nucleic acid encoding one of the 2029 (5.4 x 1037) unique amino acid sequences. The claim does not limit the function of the peptide encoded by the nucleic acid.
Claim 29 is drawn to a method of making one of the 2029 (5.4 x 1037) unique amino acid sequences of claim 1 by fragment ligation. The claim does not limit the function of the peptide encoded by the nucleic acid.
State of the prior art
The entire genus of claimed amino acid sequences are not known in the art. The characterized embodiment, Recifin A (SEQ ID NO: 1), adopts a fold comprising a four strand anti-parallel b-sheet and two helical turns stabilized by a complex disulfide bond network that creates an embedded ring around one of the strands. Applicants have named this fold a “Tyr-lock peptide” and state that it is a novel fold not previously reported in the art (specification [0066]). Owing to the novelty of the fold, there is no established consensus sequence for the Tyr-lock peptide fold in the art.
The prior art does not include a single FDA-approved tyrosyl-DNA phosphodiesterase I (TDP1) inhibitor for cancer treatment.
Tyrosyl-DNA phosphodiesterase I (TDP1) is a eukaryotic DNA repair enzyme that catalyzes the hydrolysis of phosphodiester bonds that covalently link adducts to DNA-ends. These DNA-adducts include small adducts such as oxidized nucleotides, RNA, and non-canonical nucleoside analogs, and large adducts, such as chemotherapy drug-stabilized topoisomerase-DNA covalent complexes. The prior art has focused on the search of TDP1 inhibitors as a means to combat cancer drug resistance. In a 2019 review, Brettrager et al. discuss two strategies for TDP1 inhibition: catalytic inhibition, and poisoning which comprises stabilizing the enzyme-DNA adduct thereby turning TDP1 into a cellular toxin, similar to topoisomerase inhibitors (Figure 1). There are no known inhibitors in the prior art that act according to the poisoning strategy.
The instant specification reports in [0067] that Recifin A appears to function as TDP1 inhibitor by a mechanism not previously reported in the prior art.
Level of predictability in the art
The specification provides evidence for a high level of complexity and unpredictability in the art:
- Recifin A increases the Km of full-length TDP1, a characteristic of competitive inhibitors. However, Recifin A is inactive against an enzymatically active but truncated form of the protein, with an identical active site, a characteristic of allosteric inhibition. Recifin A increases the Vmax of TDP1, a characteristic of enzyme activation. Taken together, these observations suggest a novel mechanism for the recifin A- TDP1 interaction (specification [0164]). A novel mechanism of TDP1 inhibition is, by definition, not predictable from the prior art.
- Although important, the major topological features present in the first 147 amino acids of TDP1 (deleted from the truncated variant) have not been resolved in a published crystal structure. Several potential post-translational modification sites including phosphorylation of serine 81 and SUMOylation of lysine 111, may be contribute to TDP1 regulation (specification [0164]). This lack of structural and structure-function information in the art complicates the understanding of the Recifin A-TDP1 interaction.
- The truncated analogue recifin 3-42, was found to have no TDP1 inhibitory activity (specification [0178]), an effect that was not predicted. The fact that deletion of two amino acid residues of 42 can completely disrupt activity points to a high degree of unpredictability in the structure-function relationship of Recifin A. This observation is consistent with Recifin A being a first in class inhibitor.
- A single amino acid substitution, [Ala6]Recifin leads to misfolding (specification [0178]). The fact that substitution of a single amino acid residue of 42 can completely disrupt the folding of the peptide points to a high degree of unpredictability in the primary structure-tertiary structure relationship of Recifin A. Complexity and unpredictability in the protein folding art is well-established. In addition, given that Recifin A adopts a novel fold, the Tyr-Lock, it is not surprising that there is a high degree of unpredictability associated with the primary structure-tertiary structure relationship.
The prior art in general points to a high degree of unpredictability:
- As stated above, the entire genus of claimed amino acid sequences are not known in the art. Owing to the novelty of the fold, there is no established consensus sequence for the Tyr-lock peptide fold in the art. As a result, it is not possible to predict based on the prior art how changing any particular amino acids in Recifin A will affect the Tyr-lock fold or whether any particular sequence within the scope of the claim will have the Tyr-lock fold.
- Owing to the novelty of the mechanism of action for Recifin A, it is not possible to predict based on the prior art how changing any particular amino acids in Recifin A will affect the TDP1 inhibitory activity or whether any particular sequence within the scope of the claim will have the TDP1 inhibitory activity.
- The prior art does not include a single FDA-approved tyrosyl-DNA phosphodiesterase I (TDP1) inhibitor for cancer treatment. Even if a particular sequence within the scope of the claim has TDP1 inhibitory activity, it is not possible to predict, which cancers, if any, could be treated or preventing with the peptide.
Level of skill in the art
The level of skill in the art with respect to the use of the novel class of Tyr-lock peptides is low given that this invention represents the first disclosure in the art of this class of peptides.
Level of guidance in the specification
The specification does not describe a general correlation between structure and function for the claimed genus. The role of each of the amino acids of 42 amino acid in Recifin A and in the broadest genus of SEQ ID NO: 11 on TDP1 inhibition and/or treatment or prevention of cancer are not described. As a result, it is impossible to predict, based on the specification, how changing any position will affect the claimed function.
Presence of working examples
The specification does not include a single reduction to practice of a claimed peptide inhibiting TDP1 in a mammal or treating or preventing any type of cancer.
Quantity of experimentation
The scope of the claimed peptides is enormous. That fact combined with zero reduction to practice in the specification, the level of unpredictability and complexity in the art, the relative skill in the art, and the lack of specific guidance in the specification, poses an undue burden of experimentation on one of ordinary skill in the art seeking to use the claimed peptide and practice the claimed methods. The specification is an invitation to undertake a research program to identify a valid use for the peptides and to identify which peptides, if any, can be used to practice the claimed methods. As such, the specification fails to meet the enablement provision of 35 U.S.C. 112(a).
Claims 19 and 22-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
The claim does not have an working examples for a method of treating or preventing cancer or inhibiting TDP1 in a mammal. As discussed above the claim scope is enormous given the breadth of structural limitations in the claims. Therefore, the instant specification has failed to meet the written description requirement by actual reduction to practice of a representative number of species alone.
The specification discloses the complete structure of Recifin A and several analogues presented in Table 8.
The data presented in the specification raise more questions about the physical properties of the genus than they answer. The data do not suggest the physical basis for the claimed activity and therefore do not describe which substitutions, deletions or additions could be made while preserving function. Understanding the physical basis for the claimed activity is critical to determining which of the sequences that meet the structural requirements of the genus also meet the functional requirements of the genus.
The specification provides evidence for a high level of complexity and unpredictability in the art:
- Recifin A increases the Km of full-length TDP1, a characteristic of competitive inhibitors. However, Recifin A is inactive against an enzymatically active but truncated form of the protein, with an identical active site, a characteristic of allosteric inhibition. Recifin A increases the Vmax of TDP1, a characteristic of enzyme activation. Taken together, these observations suggest a novel mechanism for the recifin A- TDP1 interaction (specification [0164]). A novel mechanism of TDP1 inhibition is, by definition, not predictable from the prior art.
- Although important, the major topological features present in the first 147 amino acids of TDP1 (deleted from the truncated variant) have not been resolved in a published crystal structure. Several potential post-translational modification sites including phosphorylation of serine 81 and SUMOylation of lysine 111, may be contribute to TDP1 regulation (specification [0164]). This lack of structural and structure-function information in the art complicates the understanding of the Recifin A-TDP1 interaction.
- The truncated analogue recifin 3-42, was found to have no TDP1 inhibitory activity (specification [0178]), an effect that was not predicted. The fact that deletion of two amino acid residues of 42 can completely disrupt activity points to a high degree of unpredictability in the structure-function relationship of Recifin A. This observation is consistent with Recifin A being a first in class inhibitor.
- A single amino acid substitution, [Ala6]Recifin leads to misfolding (specification [0178]). The fact that substitution of a single amino acid residue of 42 can completely disrupt the folding of the peptide points to a high degree of unpredictability in the primary structure-tertiary structure relationship of Recifin A. Complexity and unpredictability in the protein folding art is well-established. In addition, given that Recifin A adopts a novel fold, the Tyr-Lock, it is not surprising that there is a high degree of unpredictability associated with the primary structure-tertiary structure relationship.
The prior art in general points to a high degree of unpredictability:
- As stated above, the entire genus of claimed amino acid sequences are not known in the art. Owing to the novelty of the fold, there is no established consensus sequence for the Tyr-lock peptide fold in the art. As a result, it is not possible to predict based on the prior art how changing any particular amino acids in Recifin A will affect the Tyr-lock fold or whether any particular sequence within the scope of the claim will have the Tyr-lock fold.
- Owing to the novelty of the mechanism of action for Recifin A, it is not possible to predict based on the prior art how changing any particular amino acids in Recifin A will affect the TDP1 inhibitory activity or whether any particular sequence within the scope of the claim will have the TDP1 inhibitory activity.
- The prior art does not include a single FDA-approved tyrosyl-DNA phosphodiesterase I (TDP1) inhibitor for cancer treatment. Even if a particular sequence within the scope of the claim has TDP1 inhibitory activity, it is not possible to predict, which cancers, if any, could be treated or preventing with the peptide.
As described above there is a high degree of unpredictability in the prior art with respect to the claimed peptides, TDP1 inhibition, and treatment and prevention of cancer. For all of the reasons presented above, one of ordinary skill in the art would not know which of the countless peptides that meet the structural requirements of the claims would also be able to perform the complicated claimed functions of pharmaceutical use, inhibiting TDP1 in a mammal, and treating or preventing cancer. The specification does not make clear which peptides are in the genus and which are not because it does not describe the physical basis for the claimed activity. In other words, the specification does not describe which peptides to make.
For these reasons, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654